Subjects

Purpose: Survival in Rett syndrome (RTT) remains unclear. Although early estimates were grim, more recent data suggest that survival into adulthood is typical. We aimed to define survival in RTT more clearly and identify risk factors for early death.
Methods: Participants with clinical RTT or Methyl CpG Binding Protein 2 mutations without clinical RTT were recruited through the RTT Natural History study from 2006 to 2015. Clinical details were collected, and survival was determined using the Kaplan-Meier estimator. Risk factors were assessed using Cox proportional hazards models.
Results: Among 1189 valid participants, 51 died (range 3.9–66.6 years) during the 9-year follow-up period. Those who died included 36 (3.9%) classic RTT females, 5 (5.9%) atypical severe RTT females, 1 (2.4%) non-RTT female, the single atypical severe male, 6 (30%) non-RTT males, and 2 (7.1%) DUP males. All atypical mild RTT females, DUP females and the single classic RTT male remain alive. Most deaths were due to cardiorespiratory issues. Only one died due to severe malnutrition, scoliosis, and extreme frailty. Survival for classic and atypical RTT was greater than 70% at 45 years. Overall severity and several modifiable risk factors, including ambulation, weight, and seizures, were associated with mortality in classic RTT.
Conclusions: Survival in to the 5th decade is typical in RTT, and death due to extreme frailty has become rare. While the leading cause of death remains cardiorespiratory compromise, many risk factors for early death are modifiable. Intense therapeutic approaches could further improve the prognosis for patients with RTT.